This Phase I SBIR grant application aggressively targets the next steps in the development of lNCELL's oral smallpox vaccine. It builds on successful preliminary studies to develop the raw materials and do in vitro and formulation studies as a prelude to successfully immunizing rabbits and sheep with the oral vaccine. The intent is to continue development of an oral smallpox vaccine that will be safe, easily administered, reasonably priced, rapidly developed, and have a long shelf life. The project has three Specific Aims: (1) Perform animal efficacy studies to show that orally immunized animals can be protected from challenge with a virulent poxvirus; (2) Refine Vaccine Manufacturing and Seek Regulatory Approvals to include validating methods and defining SOPs to expand the cell cultures, concentrate and re-suspend the virus, and validate the virus-excipient-adjuvant oral formulation to assure safety, efficacy and potency of the final product; and (3) Prepare for the First Clinical Trial that will be a Phase I/II study of the oral vaccine in human subjects. The Approaches to each Specific Aim are delineated below. Phase II will be continuing work toward obtaining a licensed vaccine product and will include the clinical trials.